This postdoctoral fellowship proposal outlines plans to use the organism Caenorhabditis elegans to identify genes involved in the pathogenesis of obesity and diabetes. Obesity and type 2 diabetes are extremely prevalent, highly associated diseases that cost the US more than $132 billion in 2002, and produce an even greater cost on society in terms of life-years lost. Specific aims are to use genomics (RNA interference) and forward genetics together with newly-available, high-throughput technology to perform saturating screens for novel genes which, when inactivated, cause defects in neuroendocrine regulation of body fat content or mitochondrial biogenesis. Genes emerging from the screens with close human homologues will be the subject of further study, since both dysregulated fat metabolism and mitochondrial dysfunction have been clearly implicated in the pathogenesis of type II diabetes. As many known genes important in human diabetes also cause aging, stress resistance or reproductive defects when mutated in C. elegans, assays for these pleiotropies will be conducted for each novel gene identified to affect fat or mitochondria. Mutants receiving priority scores in these assays will have energy homeostasis defects characterized in detail by quantitative assays for lipid content, food consumption, and energy expenditure. Genetic epistasis will identify which genes operate within known pathways or novel pathways regulating energy homeostasis. The tissue of expression and cell type of action will be established for interesting genes by transgenic reporter and tissue-specific rescue constructs. For the most promising fat and mitochondrial mutants, metabolomic profiling using tandem mass spectrometry and microarray mRNA profiling analysis will be conducted to further explore the molecular nature of metabolic defects. Finally, in order to identify possible obesity or diabetes therapeutics, a small-molecule library will be screened for compounds that reverse mutant phenotypes, i.e. obesity or mitochondrial defects. The ultimate goals of this work are to identify and characterize genes central to the pathogenesis of obesity and diabetes, to identify possible therapeutic molecules, and to create a platform to expand these efforts in the future. PUBLIC HEALTH RELEVANCE: Obesity and type 2 diabetes are tightly linked diseases well recognized to be among the leading causes of premature illness and death. Over one billion people are overweight and more than 200 million have diabetes worldwide. The proposed research fellowship aims to identify novel genes involved in the development of obesity and diabetes and possible drugs to fight these devastating diseases, using new technology and a genetic system in which the role of every single gene can be studied systematically.